Members of the epidermal growth factor (EGF) family of ligands and their receptors regulate migration and growth of intestinal epithelial cells. However, our understanding of the signal transduction pathways determining these responses is incomplete. In this study we tested the hypothesis that p38 is required for EGF-stimulated intestinal epithelial monolayer restitution. EGFstimulated migration in a wound closure model required continuous presence of ligand for several hours for maximal response, suggesting a requirement for sustained signal transduction pathway activation. In this regard, prolonged exposure of cells to EGF activated p38 for up to 5 h. Furthermore genetic or pharmacological blockade of p38 signaling inhibited the ability of EGF to accelerate wound closure. Interestingly p38 inhibition was associated with increased EGF-stimulated ERK1/ ERK2 phosphorylation and cell proliferation, suggesting that p38 regulates the balance of proliferation/migration signaling in response to EGF receptor activity. Activation of p38 in intestinal epithelial cells through EGF receptor was abolished by blockade of Src family tyrosine kinase signaling but not inhibition of phosphatidylinositol 3-kinase or protein kinase C. Taken together, these data suggest that Src family kinase-dependent p38 activation is a key component of a signaling switch routing EGF-stimulated responses to epithelial cell migration/restitution rather than proliferation during wound closure.Appropriate regulation of cell migration is critical for maintenance of a healthy intestinal epithelial lining in at least two ways. The continuously renewing monolayer of cells covering the gastrointestinal tract undergoes complete turnover every few days in a process that involves the movement of newly generated cells from the proliferative compartment in the lower crypts to the small intestinal villi or colonic surface epithelia (1, 2); thus, orderly cell migration contributes to proper morphology and function of the gastrointestinal tract in the disease-free state. Furthermore the ability of epithelial cells to migrate and close a wound in the mucosal lining allows for restitution of the epithelium much more rapidly than by enhanced proliferation and is thus an early response for maintenance of barrier and absorptive functions in the face of environmental or inflammatory damage. Increased cell migration has been observed in experimentally injured epithelia (3-5) as well as in disease states such as intestinal mucosal ulceration (6 -8) and inflammatory conditions (9 -11). While the importance of cell motility in the dynamic maintenance of the gastrointestinal tract is clear, the molecular mechanisms regulating intestinal cell migration are not yet fully understood.One regulatory mechanism influencing intestinal epithelial cell migration is signaling initiated by soluble growth factors, including epidermal growth factor (EGF).1 EGF is the canonical member of a family of peptide growth factors (also including betacellulin, heparin-binding EGF-like growth fact...

Ischemia-or toxin-induced acute kidney injury is generally thought to affect the cells of the proximal tubule, but it has been difficult to define the involvement of other tubular segments because of the widespread damage caused by ischemia/reperfusion or toxin-induced injury in experimental models. For evaluation of whether thick ascending limb (TAL)-specific epithelial injury results in acute kidney injury, a novel transgenic mouse model that expresses the herpes simplex virus 1 thymidine kinase gene under the direction of the TAL-specific Tamm-Horsfall protein promoter was generated. After administration of gancyclovir, these mice demonstrated apoptosis only in TAL cells, with little evidence of neutrophil infiltration. Compared with control mice, blood urea nitrogen and creatinine levels were at least five-fold higher in the transgenic mice, which also developed oliguria and impaired urinary concentrating ability. These findings suggest that acute injury targeted only to the TAL is sufficient to cause severe acute kidney injury in mice with features similar to those observed in humans. 19: 153819: -154619: , 200819: . doi: 10.1681 Acute kidney injury (AKI), which contributes significantly to morbidity and mortality among hospitalized patients, 1 is frequently multifactorial, 2 with ischemia and nephrotoxins being the most common causes. Regardless of cause, histologic findings include dilated and flattened epithelium, loss of tubular epithelial cells, and the presence of TammHorsfall protein (THP)-rich casts. Frank necrosis is not usually apparent, and apoptotic cells are consistently found in both ischemic and nephrotoxic forms of clinical AKI. 3,4 At the cellular level, actin cytoskeletal abnormalities lead to loss of cell polarity and relocation of cell adhesion molecules. 5,6 Endothelial dysfunction and inflammation are present, although morphologic changes are subtle. 7,8 A key unanswered question in AKI is how the kidney protects itself from devastating losses of body fluids as a result of the failure of glomerular ultrafiltrate reabsorption. One proposed mechanism is tubuloglomerular feedback (TGF), whereby increased distal delivery of solutes to the macula densa results in feedback signals to the glomerulus to decrease GFR by afferent arteriole constriction. After injury, tubular epithelial cell reabsorption of sodium is impaired, which results in increased distal delivery of NaCl and subsequent activation of TGF. The decreased renal blood flow and GFR result in oliguria and, in severe cases, anuria. This J Am Soc Nephrol

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